The epidemiology of oral cancer has clearly demonstrated that its principal etiology is smoking and alcohol consumption, with over 75% of all oral cancer in the United States attributable to these two avoidable risk factors. At the same time, only a relatively small proportion of exposed individuals develop this disease. Elucidation of the factors that contribute to susceptibility to this disease will be crucial in developing novel intervention and prevention strategies. The role genetic susceptibility plays in explaining variation in the patterns of occurrence of exposure-related cancers is advancing rapidly. Much of the research has focused on lung cancer and genes which code for enzymes that either activate or inactivate xenobiotic compounds. Since the enzymes are involved inactivation and deactivation of tobacco and alcohol-related carcinogens, it has been hypothesized that they may influence cancer susceptibility. Polymorphisms in many of these genes have been identified and associated with an increased risk for lung cancer. In addition these genes appear to further alter cancer risk by level of cigarette smoking. Since tobacco carcinogens are clearly associated with oral cancer carcinogenesis, investigation into the role that genetic susceptibility has in oral cancer development is warranted. We propose a case-control molecular epidemiologic study in the greater Boston metropolitan region to investigate the role that genetic polymorphisms in metabolic enzymes have in the development of oral cancer. This project will focus on the relationship between oral cancer, the established risk factors, and diet. Speciflcally, we will investigate the association between oral cancer, smoking levels, alcohol ingestion, diet, and the presence of specific genetic polymorphisms of metabolic enzymes. We will establish a DNA bank, including obtaining paraffin blocks of tumors for future studies of somatic genetic alterations, and estimate the prevalence if genetic polymorphisms in two cytochrome P450 genes (CYPL4I and CYP2E 1), three glutathione 5-transferases (GSTMI, GS7TI, GSTP 1), the alcohol dehydrogenase type 3 (ADH3), and the methylenetetrahydrofolate reductase (MTHFR) gene. Previous associations of these polymorphisms with lung cancer or colon cancer are not readily generalizable to oral cancer without additional works such as we propose here. These finding should lead to an improved characterization of high risk individuals for whom aggressive preventive measures may be targeted. Our DNA bank and comprehensive epidemiologic approach will also provide an invaluable resource for continuing studies of the molecular and genetic epidemiology of oral cancer.